The protein kinases represent a large family of proteins that play a central role in the regulation of a wide variety of cellular processes and maintenance of cellular function. A partial, non-limiting, list of these kinases include: non-receptor tyrosine kinases such as the Tec family (BTK, ITK, Tec, ETK/BMX & RLK/TXK), Janus kinase family (Jak1, Jak2, Jak3 and Tyk2); the fusion kinases, such as BCR-Abl, focal adhesion kinase (FAK), Fes, Lck and Syk; receptor tyrosine kinases such as epidermal growth factor receptor (EGFR), the platelet-derived growth factor receptor kinase (PDGF-R), the receptor kinase for stem cell factor, c-kit, the hepatocyte growth factor receptor, c-Met, and the fibroblast growth factor receptor, FGFR3; and serine/threonine kinases such as b-RAF, mitogen-activated protein kinases (e.g., MKK6) and SAPK2β. Aberrant kinase activity has been observed in many disease states including benign and malignant proliferative disorders as well as diseases resulting from inappropriate activation of the immune and nervous systems. The novel compounds of this invention inhibit the activity of one or more protein kinases and are, therefore, expected to be useful in the treatment of kinase-mediated diseases.
Bruton's tyrosine kinase (BTK) is a non-receptor tyrosine kinase with a key role in immunoreceptor signaling (BCR, FcεR, FcγR, DAP12, Dectin-1, GPVI, etc.) in a host of hematopoietic cells including B cells, platelets, mast cells, basophils, eosinophils, macrophages and neutrophils as well as osteoclasts involved in bone destruction (for reviews, see Brunner et al., 2005 Histol. Histopathol., 20:945, Mohamed et al., 2009 Immunol. Rev., 228:58). Mutations in BTK are known to lead to X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency (Xid) in mice, which are characterized by limited B-cell production & reduced antibody titers (Lindvall et al., 2005 Immunol. Rev., 203:200). The combined action of BTK in multiple cell types makes it an attractive target for autoimmune disease. BTK is related with sequence homology to other Tec family kinases (ITK, Tec, ETK/BMX & RLK/TXK).
In B-lymphocytes, BTK is required for B-cell development and for Ca2+ mobilization following of B-cell receptor (BCR) engagement (Khan et al., 1995 Immunity 3:283; Genevier et al., 1997 Clin. Exp. Immun., 110:286) where it is believed to downstream of Src family kinases (such as Lyn), Syk & PI3K. BTK has been shown to be important for both thymus-dependent and thymus-independent type 2 responses to antigens (Khan et al., Immunity 1995, 3:283). In mast cells, studies using BTK mouse knock-outs (Hata et al., 1998 J. Exp. Med., 187:1235; Schmidt et al., 2009 Eur. J. Immun., 39:3228) indicate a role for BTK in FcεRI induced signaling, histamine release & production of cytokines such as TNF, IL-2, & IL-4. In platelets, BTK is important for signaling through the glycoprotein VI (GPVI) receptor that responds to collagen and has been shown to promote platelet aggregation and contribute to cytokine production from fibroblast-like synoviocytes (Hsu et al., 2013 Immun. Letters, 150:97). In monocytes and macrophages, the action of BTK in invoked in FcγRI induced signaling and may also have role in Toll-Like Receptor-induced cytokine responses including TLR2, TLR4, TLR8 & TLR9 (Horwood et al., 2003 J. Exp. Med., 197:1603; Horwood et al., 2006 J. Immunol., 176:3635; Perez de Diego et al., 2006 Allerg. Clin. Imm., 117:1462; Doyle et al., 2007 J. Biol. Chem., 282:36959, Hasan et al., 2007 Immunology, 123:239; Sochorava et al., 2007 Blood, 109:2553; Lee et al., 2008, J. Biol. Chem., 283:11189).
Therefore, inhibition of BTK is expected to intervene at several critical junctions of the inflammatory reactions resulting in an effective suppression of autoimmune response. As such diseases involving B-cell receptor activation, antibody-Fc receptor interactions & GPVI receptor signaling may be modulated by treatment with BTK inhibitors. BTK inhibition is likely to act on both the initiation of autoimmune disease by blocking BCR signaling and the effector phase by abrogation of FcR signaling on macrophages, neutrophils, basophils, and mast cells. Furthermore, blocking BTK would provide additional benefit via inhibition of osteoclast maturation and therefore attenuate the bone erosions & overall joint destruction associated with rheumatoid arthritis Inhibiting BTK may be useful in treating a host of inflammatory and allergic diseases—for example (but not limited to), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS) and type I hypersensitivity reactions such as allergic rhinitis, allergic conjunctivitis, atopic dermatitis, allergic asthma and systemic anaphylaxis. For a review on targeting BTK as a treatment for inflammatory disorders and autoimmunity as well as leukemias and lymphomas, see Uckun & Qazi, 2010 Expert Opin. Ther. Pat., 20:1457. Because BTK is highly expressed in cancers of the hematopoietic system & BTK-dependent signaling in believed to be disregulated there, BTK inhibitors are expected to be useful treatments for B-cell lymphomas/leukemias & other oncologic disease—for example (but not limited to) acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma (NHL), small lymphocytic lymphoma (SLL), and acute myeloid leukemia (for review, see Buggy & Elias 2012 Int. Rev. Immunol. 31:119). Taken together, BTK inhibitors provide a strong method to treat a host of inflammatory diseases and immunological disorders as well as hematologic cancers.